Synergistic Interactions Between Gut and Intratumoral Microbiota: A New Perspective on the Oncogenesis and Treatment of Colorectal Cancer.

Colorectal cancer, a common malignancy of the digestive system with high morbidity and mortality, is closely associated with the microbiota. Recent studies have revealed that the gut microbiota and intratumoral microbiota are not only anatomically connected but also functionally synergistic. Together, they shape the tumor microenvironment and profoundly influence CRC initiation, progression, immune evasion, metastasis, and therapeutic response. Centered on the concept of the "gut-tumor microbiota axis," this review summarizes the origins, dynamic alterations, and functional roles of both microbial communities in CRC. It highlights their metabolic outputs, regulatory effects on tumor cell behavior and the immune microenvironment, and their implications in chemotherapy, immunotherapy, and microbiota-based engineered therapies. Coordinated modulation of gut and intratumoral microbiota may offer novel avenues for precision interventions, providing new therapeutic strategies and enhancing the efficacy of current treatments for CRC.Colorectal cancer (CRC) is a prevalent malignancy of the digestive system characterized by high morbidity and mortality. Accumulating evidence indicates that both the gut microbiota and intratumoral microbiota are integral to CRC pathogenesis and therapeutic outcomes. Understanding their interactions provides new insights into tumor biology and treatment strategies.This review synthesizes recent findings on the composition, origin, and dynamic alterations of gut and intratumoral microbiota in CRC. It focuses on their metabolic outputs, immunoregulatory mechanisms, and their collective influence on tumor initiation, progression, immune evasion, metastasis, and therapeutic response. Publications related to microbiota-tumor interactions and microbiota-based interventions were systematically analyzed and summarized. The gut and intratumoral microbiota form an interconnected and functionally synergistic ecosystem, jointly shaping the tumor microenvironment. These microbial communities modulate metabolic pathways, immune signaling, and tumor cell behavior, thereby influencing the efficacy of chemotherapy, immunotherapy, and emerging microbiota-based engineered therapies. Recent studies highlight the translational potential of targeting the "gut-tumor microbiota axis" to enhance treatment precision and overcome therapeutic resistance.The bidirectional interplay between the gut and intratumoral microbiota represents a critical determinant of CRC development and treatment responsiveness. Coordinated modulation of both microbial compartments may enable precision medicine approaches, offering novel therapeutic avenues and improving clinical outcomes in CRC patients.